Periprosthetic infection of metallic implants is one of the most serious complications in orthopedic surgeries and its incidence has seen a recent nationwide upward trend despite rigorous prophylaxis and surgical approaches. Biofilm formation surrounding the implant is a common threat that makes these serious local infections both more likely to occur and more difficult to eradicate. Current approaches in improving the anti-fouling property of implant surfaces or locally delivering antibiotics have shown some short-term benefits, but the long-term outcomes of these approaches are not satisfactory. The goal of the proposed study is to address the challenge of periprosthetic infections by synergistically affording metallic implant surfaces with stable anti- fouling and sufficient bactericidal propertie without compromising osteointegration. This will be realized by grafting functional polymer brushes containing zwitterionic and vancomycin-bearing motifs with modularly tunable chemical compositions, molecular weights, and spatial arrangements of the functional motifs from metallic alloy surfaces using surface initiated living atom-transfer radical polymerization (SI-ATRP) and bioorthogonal azide/alkyne cycloaddition click chemistry. The choice of the zwitterionic motif is motivated by their stable anti-fouling properties and our recent discovery of their novel role as potent mediators of biomineralization. In Aim 1, we will surface-graft a library of homopolymers, random and block copolymers with modularly presented anti-fouling and bactericidal functional motifs from commercial Ti6Al4V substrates using the robust SI-ATRP and click chemistry. The properties and robustness of the coatings are characterized and validated by X-ray photoelectron spectroscopy, water contact angle measurements, thermo-gravimetric analysis/gel permeation chromatography as well as surface scratch test. In Aim 2, we will screen for the most effective bactericidal and anti-fouling yet cytocompatible surface brush compositions by quantification of in vitro inhibition of Staphylococcus aureus (S. aureus) cultures by, non-specific protein absorptions on, and viability/proliferation of adherent bone marrow stromal cells on the modified surfaces. In Aim 3, the top functional homopolymer, block and random copolymer surface brush compositions chosen from Aim 2 are applied to Ti6Al4V intramedullary (IM) rods. The surface modified IM rods, along with unmodified control and that modified with a monolayer of vancomycin, are implanted in rat femoral medullary canals inoculated with either S. aureus or saline (uninfected control). The efficacy of the surface polymer brush coatings in reducing short-term (3 weeks) and longer-term (up to 6 months) periprosthetic infections are evaluated by quantification of S. aureus adhered on the retrieved IM rod, sequestrum formation and femur widening/cortex thinning (by microCT), and the failure torque of explanted femurs. These outcomes are scored to guide the selection of the surface brush composition affording the most sustained inhibition to periprosthetic infections and minimal perturbation to normal femoral morphology and mechanical integrity. Biocompatibility of the surface brush compositions are also examined by the pathology of vital/scavenger organs and femurs (for signs of osteolysis, acute/chronic inflammatory responses and allergic reactions to the coating) of the rats receiving implants without bacterial inoculum. Successful completion of this study is expected to identify a biocompatible surface polymer brush composition affording sustained protection against / inhibition of periprosthetic infections that can be broadly applied o a wide range of metallic surgical implants.